Novel 1-benzoyloxy-2-lower alkylamino-benzocycloalkane derivatives

ABSTRACT

BENZENE   WHEREIN R1 REPRESENTS HYDROGEN ATOM OR A LOWER ALKYL GROUP; R2 REPRESENTS A LOWER ALKYL GROUP; R3, R4 AND R5 ARE THE SAME OF DIFFERENT FROM EACH OTHER AND EACH REPRESENTS A HYDROGEN ATOM, A HALOGEN ATOM, A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP, PHENYL GROUP, AMINO GROUP, A LOWER ALKYLAMINO GROUP, AN ACYLAMINO GROUP OR NITRO GROUP; N IS AN INTEGER OF 1-3, AND THE NON-TOXIC MINERAL ACID SALTS THEREOF. THE COMPOUNDS OF THIS INVENTION HAVE A LOCAL ANESTHETIC AND ANALGESIC ACTION AND ARE ALSO USEFUL IN PROMOTING THE FUNCTION OF THE STOMACH. THE 1-BENZOYLOXY-2-LOWER ALKYLAMINOBENZOCYCLOALKANE DERIVATIVES REPRESENTED BY THE FORMULA 1,2-(-CH(-O-CO-(R3,R4,R5-PHENYL)-CH(-N(-R1)-R2)-(CH2)N-)-

United States Patent O 3,823,181 NOVEL l-BENZOYLOXY-Z-LOWER ALKYLAMINO- BENZOCYCLOALKANE DERIVATIVES Masuo Murakami and Kozo Takahashi, Tokyo, Yasubumi Hirata, Ageo, Kazuo Kubo, Urawa, Toshiyasu Mase and Isao Yanagisawa, Tokyo, and Masaaki Takeda and I-Iiroki Ino, Ageo, Japan, assignors to 'Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan No Drawing. Filed June 14, 1972, Ser. No. 262,623 Claims priority, application Japan, June 22, 1971, 46/44,491; Dec. 6, 1971, 46/98,495; Dec. 10, 1971, 46/100,049

Int. Cl. C07c 93/20 US. Cl. 260-477 6 Claims f ABSTRACT OF THE DISCLOSURE The l-benzoyloxy-Z-lower alkylaminobenzocycloalkane derivatives represented by the formula f R. CH7) :1

wherein R represents hydrogen atom or a lower alkyl group; R represents a lower alkyl group; R R and R are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, phenyl group, amino group, a lower alkylamino group, an acylamino group or nitro group; n is an integer of 1-3, and the non-toxic mineral acid salts thereof.

' The compounds of this invention have a local anesthetic and analgesic action and are also useful in promoting the function of the stomach.

DISCLOSURE OF THE INVENTION The present invention relates to novel benzocycloalkane derivatives. More particularly, the invention relates to the l-benzoyloxy-Z-lower alkylaminobenzocycloalkane derivatives represented by the formula OCO- Br I C I): (III) wherein R represents a hydrogen atom or a lower alkyl group; R represents a lower alkyl group; R R and R are the same or different from each other and each represents hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, phenyl group, amino group, a

lower alkylamino group, an acylamino group, or nitrogroup; n is an integer of 1-3; and (D and (2) of said formula are numberings employed in the specification of this invention and the non-toxic mineral acid salts thereof.

The l-benzoyloxy-Z-lower alkylaminobenzocycloalkane derivatives of the formula (III) and the non-toxic mineral acid salts thereof, which are the compounds of this invention, are novel compounds and have excellent local anesthetic action. In particular, the compounds of this invention can maintain a local anesthetic action even in the pH range of the gastric juice and thus they are quite suitable for curing gastritis and duodenitis. Moreover, the compounds having an action of stimulating the gastic motility ice and thus they are also suitable for curing, particularly, they lack tonicity in the stomach.

Procaine, lidocaine, etc., have, hitherto, been known as the compounds having the local anesthetic action but it has been difficult to remove such gastric symptoms caused by acute or chronic gastritis, such as a stomach ache, a heavy feeling on stomach, belching, nausea, etc., by those conventional compounds. This is believed to be due to the fact that said compounds lose their local anesthetic activity at the gastric pH (about 2).

Oxethazine which has corrected this fault has been widely marketed. Although, oxethazaine has high local anesthetic action at the gastric pH as compared with aforesaid compounds, the action thereof is insufficient for relieving the ache caused by a dueodenal ulcer and also its local anesthetic action is unduly delayed (Progress in Medicinal Chemistry, 3, 387 (1963)).

Recently, I. M. Glassman et al. have developed N,N- diethyl-fi-benzoyloxyphenethylamine having excellent local anesthetic action at the gastric pH (US. Pat. No. 3,499,-'

28nd but this compound has not yet been sold or marete The inventors have found that even if medicines have a local anesthetic action, they are insufiicient for curing the gastric symptoms caused by gastritis and for the purpose they must have an effect of stimulating the gastric motility and as the results thereof the inventors have discovered that the compounds of the formula (III) of this invention have an excellent local anesthetic action even at the gastric pH and analgesic action and are medicaments quite suitable for curing the gastric symptoms caused by acute or chronic gastritis as compared with the known local anesthetics, N,N diethylamino-B-benzoyloxyphenethylamine, etc.

In connection with the compounds of this invention shown by the formula (III), J. von Braun et al. have reported that 1-hydroxy-2-dimethylamino Tetralin is obtained by the method shown below /C OH HN\ in sealed tube CH @3 in benzene, o

\ p-introbenzoylating CH:

CH2 Reduction OH; I

and further Z-dimethylamino-l-p-nitrobenzoyloxy Tetralin having a melting point of 112 C. is obtained by pnitrobenzoylatingthe-attetralinobtained above y am Tetralin prepared y reac mg e compo imethy ntr -taeth h b h q le T tral n e 2 a e of he f rm a (A) with V by r diicing the above product (Ber., 55, 3648 (1922)). EH

Moreover, F. Straus et al. have reported that l-hydroxy- Z-dirnethylamino '1" etrali11 iS Prepared by the method 5 NH showii'below' p v OH;

OH CH OH in a benzene at 120 Chin sealed tube was subjected to a t a benzoylation in accordance with :the report, .a benzoyl Br compound which was colored.and t-deeompose'd an" 8-- CH3 10 180 C. near the melting point of 176C. describedgm cm the report was obtained. Also, when-the compound was' subjected to ap-nitrobenzoylation, a p-nitrobe'nzo yl com- (A) (B) pound having a melting point'of 112 was obtained. The melting point of the compound 'obtained'coincides (Ber., 54, 40 (1921)). With the melting point ofthe p-nitroberizoyl compound Still further, A. Gonzalez et al., have reported that 1- described infhe voItBraun 6t P reporiand thh the hydroxy-Z-dimethylamino Tetralin is prepared by the hydfoXy-2-dlemthylamlno Tetfalln Produced y G011- h d as shown b l zalez et al. was a compound which was the same as 2-hydroxy-l-dimethylamino Tetralin.

0 In addition, by the inventors supplementary experi- 0 in Sealedtube ments, the benzoyl compound having'the melting-pointn of 176 C. (the compound was colored and decomposed-t in g g C at l78180 C. according to the inventors supplementary experiments) obtained by A. Gonzalez et al. report has been confirmed to be 24,-; benzoyloxy l-dimethylamino Tetralin hydrochloride shown by the formula" CH CHs-HCI (I)H CH:

N\ i OH: benzoylating ,Q-

o-oo by a nuclear magnetic resonance analysis, etc}..- I I As mentioned above, the compound that had-been-believed to be 1-hydroxy-2-dimethylamino-.Tetralin has, in,

fact, been confirmed to be 2-hydroxy-l-dimethylamino N Tetralin and thus it is clear that the misnamed l-benzoyl- H: oxy, l-p-nitrobenzoyloxy, or 1-p-aminobenzoyloxy-2-dimethylamino Tetralin obtained by benzoylating the above compound are, in fact, 2-benzoyloxy-, Z-p-nitrobenzoyloxy and further 1 benzoyloxy-Z-dimethylaminotetrahydro- -p-aminobenzoyloxy-l-dimethylamino Tetralin. naphthalene hydrochloride having a melting point of 176 Accordingly, although thenam'esof the compounds of C. is obtained by benzoylating the Tetralin prepared this invention of the formula (III) .1 nay be l cnown by prior ab (Ch i l Ab tr 17 3030 (1923) d A l art literature, it is clear from the report of .T. von Braun Soc. espan fis quim., 20, 534 (1922)). et al. in 1930 and the aforesaid inventors supplementary From these reports, it might appear that at least a experiments that the n y of the pe w part of the compounds of the present invention were known and collseqllellfly'compound Y ht t' publicly known. However, I. von Braun et al. who had the formula (I are novel pQ hbeen doubtful of the structure of the formula (B) as re- NOW Thflft et have recentlytsyntheslled m ported by themselves and F. Straus et a1. with regard to l'hydl'oxytetlalin y reductively acetylafing y h'."

the product obtained by the reaction of the compound imino-l-tetralou to provide 2-acetamido-1-tetralon,reduc- (A) with dimethylamine, further continued investigation hlg the tethaloh with NaBH4 .form hhm h l fj of said reaction and have found that the reaction product droxytetralm, and then releaslhg the i $39 2.

obtained through an intermediate compound having the Chem- 288 (1967))- formula (C) t o droxy-2-d1methylam1no Tetralin by reacting the 2-am'1'nol-hydroxy Tetralin obtained by the aforesaid method with formaldehyde and formic acid and further obtaining lbenzoyloxy-2-dimethylamino Tetralin by benzoylating 1- hydroxy-2-dimethylamino Tetralin thusobtained. As mentioned above, it has also been discovered that the compounds thus prepared show, unexpectedly a high local was not the 1-hydroxy-2-dimethylamino Tetralin but is in anesthetic action at the gastric pH and based on this dis- The inventors have succeeded in obtaining true l-hyfact 2-hydroxy-l-dimethylamino Tetralin (Ben, 63, 3052 covery the present invention has been attained.

(1230) Accordingly, it is apparent that also the dimeth- It shall be particularly noticed that the l-benzoyloxy-Z- ylainino compound reported by A. Gonzales et a1. is in dimethylamino Tetralin hydrochloride (correctly 2-benzofact :2 hydroxyl-dimethylamino Tetralin as it was ob- *yloxy-l-dimethylamino Tetralin hydrochloride) obtained tainedby reacting the compound (A) withdimethylamine by the method reported, by A. Gonzalez'et a1. has no local under almost the-same conditions (although the'reaction anesthetic action at the gastric pH and, also," it is clear" temperature was slightly dilferent) as reported by J. von that the present invention is not preceded by A. Gonzalez Braun et a1. v et al.-'and'J. von Braun et al. In addition, the melting In fact, when the inventors followed the method of the .point of the 1-benzoyloxy-2-dimethylamino Tetralin hy- A. 'Gonzales'et 'al. report, that is, when the hydroxydi- 7 drochloride obtained by the present inventionwas' 203 wherein R R and n are as defined above with thebenzoic acid shown by the formula wherein R", R and R are as defined above or the reactive derivative thereof at the carboxyl group.

Inthe compound of this invention having the formula (III), the compounds of this invention wherein R is an amino group can be obtained by reducing the compound where R is nitro group in a conventional manner if necessary.

Practically speaking, the reaction is conducted by reacting the compound of the formula (I) with, usually equimolar or slightly excessive molar amount of the compound of the formula (II) or the reactive derivative thereof at the carboxyl group. The reaction is conducted in water or a proper organic solvent. And when the benzoic acid, i.e. the compound of the formula (II) is used, the reaction can be conducted at room temperature in an organic solvent such as methylene chloride, chloroform, etc., under the presence of an almost equimolar amount of a carbodiimido compound such as dicyclohexylcarbodiimide. When the reactive derivative of the compound of formula (II) is an acid halide such as acid chloride, acid bromide, etc., the reaction is conducted by allowing the reactants to stand in an organic solvent such as benzene, toluene, etc., or by heating them in the solvent but a tertiary base such as pyridine, triethylamine, etc., may be added tothe reaction system. Furthermore, the reaction may be conducted by a so-called Schotten-Baumann reaction in the presence of an alkali hydroxide in an aqueous solvent- When the reactive derivative is an acid anhydride or an active ester such as p-nitrophenyl ester, etc., the reaction may be usually conducted in an organic solvent suchas chloroform, benzene, etc., at room temperature or as the case may be under heating.

The compound of the formula (III) prepared by the aforesaid-reaction may be isolated by a conventional chemical operation such as a; filtration, concentration, recrystallization, column chromatography and the like.

As the'starting" material of the formula (I) used in this invention, there are the cis-form and the trans-form according to the steric configurations of the amino group and the hydroxyl group as well as the dl-form, the op tically active d-form, and l-form. When each of the starting materials is employed, the compound having the corresponding steric and optical configuration is obtained. Also, the mixture of those isomers of the starting material are used in the reaction and the products may be separated by a fractional crystallization, column chromatography, optical resolution, etc.

Also, in the case of obtaining the compound of the formula (1H) wherein R is an amino group from the 6 compound of the formula (III) wherein R is a nitro group, the compound may be reduced by a conventional manner. For example, the reduction is carried out by heating the compound together with an iron powder and hydrochloric acid in water.

Furthermore, the compounds of this invention shown by the formula (III) may be obtained by other methods than those described above. For example, the compounds of the formula (III) may be also obtained by reacting the 2-amino 1 benzoyloxybenzocycloalkane derivatives represented by the formula wherein R R and R and n are as defined above with a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc., by a conventional manner. Also, the compounds of the formula (HI) wherein R is hydrogen atom may be prepared by reacting a compound of the formula (IV) with a lower aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, etc., to provide a corresponding Schiifs base followed by reducing. Furthermore, the compounds of the formula (111) wherein R is a lower alkyl group may be prepared by reacting the compounds of the formula (III) wherein R is hydrogen atom prepared by the above procedure and a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc.

Still further, the compounds of the formula (III) of this invention wherein R and R are a methyl group may be obtained by heating the compounds of the formula (IV) or the oxazoline derivatives represented by the formula wherein R R and R and n are as defined above together with calculated or excessive amounts of formaldehyde and formic acid.

Many of the starting materials of the formula (I) in this invention are novel compounds and may be prepared by lower alkylating the known 2-amino-1-hydroxy-benzocyloalkane derivatives (J. Chem. Soc. (c), 288 (1968) and Ann. Chem., 738, 79 (1970)) represented by the formula I) in (VI) wherein n is as defined above by a conventional way. For example, the starting materials of the formula (I) may be prepared by reacting the compounds of the formula (VI) with a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc., or by reacting the compound of the formula (V1) with a lower aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, etc., to form a corresponding Schilfs base followed by reducing. Moreover, the compounds of the formula (I) wherein R and R are a methyl group may be obtained by heating a compound of the formula (VI) together with calculated or excessive amounts of formaldehyde and formic acid.

Now, the R group .of the compounds lpf-this invention shown by. the formula (III) includes a hydrogen atom and a lower alkyl' group such as methyl group, ethyl group, isopropyl group, 'isobutyl group, tert-butyl group, amyl group, etc. Also, the R group includes a lower alkyl group such-as methyl group, ethyl group, isopropyl group, isobutyl group, tert-butyl group, andlamyl group. Also, the groups R R and R are the same or different from each other and each represents hydrogen atom; a halogen atom such as chlorine, bromine, etc.; a lower alkly group such 'as mehtyl group, ethyl group, isopropyl group, tert-butyl group, and amyl group; a lower alkoxy group such as methoxy group, ethoxy group, etc.; a substituted amino group such as monomethylamino group, monoethyl amino group, dimethylamino group, diethylamino group, acetoamino group, carbobenzoxyamino group; amino group; phenyl group; and nitro group.

The practical examples of the compounds of this invention represented by the formula (III) are;

cis-1-benzoyloxy-2-dimethylamino Tetralin, trans-1-benzoyloxy-Z-dimethylamino Tetralin, cis-l-benzoyloxy-2-dimethylaminoindane, trans-1-benzoyloxy-2-dimethylaminoindane, cis-1-benzoyloxy-Z-dimethylaminobenzocycloheptane, trans-1-benzoyloxy-2-dimethylaminobenzocycloheptane, cisl-benzoyloxy-Z-diethylamino Tetralin, cis-1-benzoyloxy-Z-dietehylaminoindane, cis-l-benzoyloxy-Z-methylamino Tetralin, cis-1-benZoyloxy-2-methylaminoindane, cis-l-benzoyloxy-Z-ethylamino T etralin, cis-1-benzoyloxy-2-ethylaminoindane, cis-l-benzoyloxy-Z-propylamino Tetralin, cis-1-p-rnethylbenzoyloxy-Z-dimethylamino Tetralin cis-1-p-methylbenzoyloxy-2-diethylaminoindane, cis-1-o-methoxybenzoyloxy-2-dimehtylamino Tetralin, cis- 1- (3 ,4,5-trimethoxy) benzoyloxy-2-dimethylamino Tetralin, cis-l-p-chlorobenzoyloxy-2-diethylaminoindane, cis- (3,4-dichloro benzoyloxy-Z-dimethylamino Tetralin, cis-1-p-nitrobenzoyloxy-2-dimethylamino Tetralin, cis-p-nitrobenzoyloxy-Z-diethylaminoindane, cis-1-p-dimethylaminobenzoyloxy-Z-dimethylamino Tetralin, cis-1-p-dimethylaminobenzoyloxy-Z-diethylaminoindane, cisl -p-acetylaminobenzoyloxy-2-diethylaminoindane, cis-1-p-aminobenzoyloxy-Z-dimethylamino Tetralin, cis-1-(4-acetamino-5-chloro-2-methoxybenzoyloxy) -2- dimethylamino Tetralin, cis-l-(2-methoxy-4-nitrobenzoyloxy)-2-dimethylamino Tetralin, cis-l-(4-amino-2-methoxybenzoyloxy)-2-dimethy1amino Tetralin, and cis-2-dimethylamino-l-(p-phenylbenzoyloxy) Tetralin.

Those compounds may be converted into the non toxic acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid.

The compounds of this invention are orally administered in the form of, e.g., tablets, capsulated form, powder, etc. The clinical dosage of the therapeutic compounds of this invention to an adult is -20 mg. and the amount of the compound is orally administered 1-3 times in a day. The dosage thereof is properly controlled by the condition and age of the patient.

In the Experiment 1 shown below, the excellent localoxyphenethylamine hydrochloride (US. Pat. No. 3,499,--

087) (sample (C)), lidocaine (sample (B)), and the 2- benzoyloxy-l-dimethylamino Tetralin hydrochloride (sampie (E) obtainedby themethod reported by; .;Gonza1e z TABLE I I (50% effective concentration at pH=6) 50% Eifective concen;

Sample: I

(A) 0.07 (0.03-0.14) (B) 0.08 (ODS-0.13) (C) 0.3 (0.2-0.45) (D) 0.8 (0.4-1.6) The confidence limit.

TABLE II.

(Inhibition percentage when the sample of 1% in concentration is used at pH=2) Sample Inhibition percentage 61 -3} c) 11:25 (D) i 10:31 Q

1 Standard error. v

In the following Experiment II, the excellent action of the sample (A) or (B) for stimulating the gastric motility at the reduction in gastric motility was compared with that of the known oxethazaine (SampleF) Experiment II After anesthetizing a dog fasted overnightby intravenously injecting 30 mg./kg. of "pentabarbital, 10 mg./ kg. of .the sample was intravenously injected in the dog or 20 mg./kg. of it was administered in the duodenum of the dog, and then the spontaneous motility of the stomach was recorded by means of an ink-writing polygraph (RM-450, made by Nihon Kohden K. K.) according tothe balloon method (Jap. J. Smooth Muscle Res, 2, 15 (1966) The results are shown in the following table.

In addition, in the table, the stimulating action of the gastric motility is denoted as when the'spontaneous motility of the stomach continued longer than ZO minutes" and is denoted as when it did not continue.

TABLE III Stimulating action oi gastric motility Sample (a) (b) No'rE.(a)=Intravenous inieetion,:and (b)=Administration to. duodenum.

9 Example 1 In 5 ml. of benzene was dissolved 3.8 g. of cis-l-hydroxy- Z-dimethylamino Tetralin and than 2 ml. of a benzene solution containing 3.1 g. of benzoyl chloride was added to the solution. The mixture was allowed to stand overnight at room temperature and then refluxed for 4 hours. The reaction mixture was cooled, the crystals thus formed were recovered by filtration, and after washing them with a small amount of benzene, they were recrystallized from an ethanolethyl acetate solvent to obtain 4.3 g. of cis-1- benzoyloxyQ-dimethylaminotetralin hydrochloride having a melting point of 203-204 C. (melting point of 223 C. by means of a Micro-Melting Point Apparatus).

NMR spectrum (D Hydrogen at the 1-position 6: 6.5 p.p.m. (doublet, =2 Hz.).

NMR spectrum of free base (CD01 Hydrogen at the 1-position 6: 6.65 p.p.m. (doublet, .T =2 Hz.).

Elemental analysis as C H N0 Cl. Calculated (percent): C, 68.77; H, 6.68; N, 4.22. Found (percent): C, 68.51; H, 6.75; N, 4.39.

Then, the hydrochloride prepared above was dissolved in water and then potassium carbonate was gradually added to the solution to obtain cis-l-benzoyloxy-Z-dimethylamino Tetralin in the form of the free base having a melting point of 74-75 C.

Elemental analysis as C H NO Calculated (percent): C, 77.26; H, 7.17; N, 4.74. Found (percent): C, 77.17; H, 6.91; N, 4.94.

Optical resolution of cis-1-benzoyloxy-Z-dimethylamino Tetralin:

Cis 1 benzoyloxy-Z-dimethylamino Tetralin was dissolved in ethanol and after adding to the solution 0,0-dibenzoyl-d-tartaric acid, the mixture was allowed to stand resulting in the formation of crystals showing ]1 =146.7 (C.=1.42, ethanol).

Also, from the mother liquor, crystals showing [a] =-i-26.55 c. =1.7s, ethanol) were obtained.

The former crystals were suspended in water and after adding to the suspension potassium carbonate, the mixture was extracted with ether. The extract was dried, mixed with ethanol and hydrochloric acid, and then the solvent was distilled off. By recrystallizing the residue from ethanol-ether, l-cis-l-benzoyloxy-2-dimethylamino Tetralin hydrochloride having a melting opint of 211- 212 C. (decomposed) was obtained.

Also, by treating the latter crystals similarly as above, d-cis-1-benzoyloxy-2-dimethylamino Tetralin hydrochloride having a melting point of 2102ll C. (decomposed) was obtained.

[a] =+l77.2 (C.=1.728, ethanol).

Production of Starting Material A mixture of 4.32 g. of cis-2-amino 1 hydroxy Tetralin hydrochloride, 1.69 g. of sodium formate, 6 g. of 98% formic acid, and 7 g. of 37% formalin was heated for 14 hours at 90-l10 C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 100 ml. of water, and then the solution was neutralized with potassium carbonate. The product was extracted from the solution with 120 ml. of chloroform, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 3.8 g. of oily cis-l-hydroxy-Z-dimethylamino Tetralin.

Other Production of Starting Material (a) In m1. of tetrahydrofuran was suspended 2 g. of trans-2-a'cetamido-l-hydroxy Tetralin and after adding to the suspension 2 g. of thionyl chloride under ice cooling, the mixture was allowed to stand for 30 minutes. By re- 10 covering the precipitates thus formed by filtration, 2 g. of cis 2-methyl-3a,4,5,9b-tetrahydronaphtho[2,l-d]oxazole hydrochloride having a melting point of l48149 C. was obtained. 7 I

Elemental analysis as C I-I NOCl. Calculated (percent): C, 64.43; H, 6.31; N, 6.26. Found (percent): C, 64.61; H, 6.38; N, 6.34.

(b) In a mixture of 3 ml. of formic acid and 3 ml. of formalin was dissolved 2.24 g. of cis-Z-methyl- 3a,4,5,9b-tetrahydronaphtho[2, l-d] oxazole hydrochloride and after adding to the solution 0.7g. of sodium formate, the mixture was heated to -105 C. for 8 hours. After the reaction was over, the reaction mixture was made alkaline by the addition of an aqueous solution of sodium hydroxide and the mixture was heated for 30 minutes at 100 C. After cooling, the reaction product was extracted three times each time with 5 ml. of chloroform. The chloroform extracts were combined and after drying the mixture over anhydrous potassium carbonate, the solvent was distilled off to obtain 1.6 g. of cis-l-hydroxy- Z-dimethylamino Tetralin having a melting point of 36- 38 C.

Elemental analysis as C12H1'1NO- Calculated (percent): C, 75.35; H, 8.96; N, 7.32. Found (percent): C, 75.24; H, 8.83; N, 7.41.

Nuclear magnetic resonance spectrum N-CH: CHa

11:5.23 (doublet, J=4.0 Hz., CDCl In addition, the absorption of trans-l-hydroxy-Z-dimethylamino Tetralin was not observed.

Example 2 In 2 ml. of benzene was dissolved 0.41 g. of trans-1- hydroxyQ-dimethylamino Tetralin and after adding to the solution 1 ml. of benzene solution containing 0.33 g.

of benzoyl chloride, the mixture was refluxed for 4 hours.

The reaction mixture was cooled and extracted with 10 ml. of water. The extract was adjusted to a weak basic state with potassium carbonate and then extracted with 10 ml. of benzene. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to provide 0.37 g. of an oily material. When the product was purified by means of a silica gel column chroma-' tography, 0.17 g. of oily trans-l-benzoyloxy-Z-dimethylamino Tetralin was obtained. Furthermore, when the product was mixed with ethanol-hydrogenchloride and then the solvent was distilled off under reduced pressure, oily trans-1-benzoyloxy-2-dimethylamino Tetralin hydrochloride was obtained.

NMR spectrum (CDCl Hydrogen at the 1-position 6: 6.70 p.p.m. (doublet, J =8 Hz.).

Elemental analysis as C H N0 Cl. Calculated (percent): C, 68.77; H, 6.68; N, 4.22. Found (percent): C, 68.92; H, 6.48; N, 4.36. I

By recrystallizing the oily product from water, crystals having a melting point of 79 C. were obtained.

Elemental analysis as C H NO Cl-H O. Calculated (percent): C, 65.23; H, 6.91; N, 4.00. Found (percent): C, 65.66; H, 6.42; N, 4.13.

Production of Starting Material To 0.45 g. of trans-Z-amino-l-hydroxy Tetralin were added 2 ml. of 85% formic acid and 2 ml. of 37% formalin and then the mixture was refluxed for 14 hours. Excessive formic acid and formalin were distilled off from the reaction mixture and the residue was dissolved in 20 ml. of water. The solution was adjusted to a weak basic state with potassium carbonate. The product was extracted with 20 ml. of chloroform and after drying the extract over anhydrous magnesium sulfate, the solvent was distilledotf toobtain 0.41 g. ofoily trans-l-hydroxy-Z-di- .i Y a iuo Tetralin. h

Example 3 'siis'peiision 1 ml. of'benzene solution "containing O.l4..g.

of-benzoyl chloride, the mixture was refluxed for 5 hours. The reaction mixture was cooled and the crystals thus formed were recovered by filtration and recrystallized from "'ethanolbenzene. 0.15 g. of cis-1-ben'zoyloxy-2 di 'methylaminoinda'n'ehydrochloride having a melting point of 220 C. was obtained.

NMR spectrum (CD01 Hydrogen at the 1-position 6: 6.9 ppm. (I=1 Hz.). Elemental analysis as C H NO Cl. Calculated (percent): C, 68.03; H, 6.34; N, 4.41. Found (percent): C, 68.21; H, 6.54; N, 4.36.

Production of Starting Material ,To 0.2 g. of cis-2-amino-1-hydroxyindane were added 1 ml. of 95% formic acid and 1 ml. of 37% formalin and the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure, the residue obtained was dissolved in 15 ml. of water, and the solution was neutralized with potassium carbonate. The product was extracted with 20 ml. of chloroform and after drying over anhydrous magnesium sulfate, the solvent was distilled off from the extract to obtain 0.18 g. of oily cis-l-hydroxy-Z-dimethylaminoindane.

Example 4 To 0.55 g. of trans-Z-amino-l-hydroxyindane were added 0.2 g. of sodium formate, 2 ml. of 85% formic acid and 1.5 ml. of 37% formalin and the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was mixed with 10ml. of water. The aqueous solution prepared above was adjusted to a Weak basic state with potassium carbonate and the product was extracted with 30 ml. of chloroform. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled oil to obtain an oily residue. The residue was dissolved in 3 ml. of pyridine and after adding to the solution 0.5 g. of benzoyl chloride, the mixture was allowed to stand overnight at room temperature. The pyridine was then distilled olf under reduced pressure, the residue was mixed with 5 ml. of water, and then the product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. An ethanol hydrogenchloride was added to the residue thus formed, the ethanol was then distilled ofl, and the residue thus obtained was recrystallized from an ethanolbenzene solvent to form 0.2 g. of trans-l-benzoyloxy-2-dimethylaminoindane hydrochloride having a melting point of 125-127 C.

NMR spectrum (CD01 Hydrogen at the 1-position 6: 6.45 ppm. (J=0-1 Hz.).

Elemental analysis as C H NO Cl. Calculated (percent): C. 68.03; H, 5.34;. N, 4.41. Found (percent): C, 67.82; H, 6.19; N, 4.57.

Example 5 In 5 ml. of dichloromethane was dissolved 0.7 g. of 1- hydroxy-Z-dimethylaminobenzocycloheptane prepared by dimethylating 2-amino-1-hydroxybenzocycloheptane and after-adding to the solution 0.6 g. of benzoyl'chloride, the mixture was refluxed for 4 hours. The solvent was distilled off from the reaction mixture and then after adding to the residue thus obtained 10 ml. of 1 N sodium carbonate, the product was extracted three times each time with. 10ml. of benzene. The benzene extracts were washed with water and dried-over anhydrous potassium carbonate, and the benzene Was distilled off. By purifying the residue by means of a silica gel column chromatography,

heptane was obtained.

Elemental analysis as C H NO Cl. Calculated (per.- cent): C, 77.63; H, 7.49; :N, 4.52. Found (percent) Example 6 5 A To 0.5 g. of 2-ethylamino-l-hydroxyindan hydrochloride was added 2 ml. of benzoyl chloride and the mixture was heated for 10 minutes to -170" C. after. cool} ing the mixture, 15 ml. of benzene and 10 ml. of water were added to the mixture followed by shaking. The aqueous layer thus formed recovered, was washed twice each time with 10 ml. of benzene, and then dried under reduced pressure. The residue thus obtained was recrystallized from an ethanol-ether solvent to obtain 0.5 g. of 1- benzoyloxy-Z-ethylaminoindane hydrochloride having a melting point of 189190 C. (decomposed).

Elemental analysis as C H NO CL Calculated (percent): C, 68.03; H, 6.34; N, 4.41. Found (percent): C, 67.89; H, 6.55; N, 4.59.

9 Example 7 In 10 ml. of benzene was dissolved 1.8 g. of 2-die'thyl amino-l-hydroxyindane prepared by ethylating 2 ethyl amino-l-hydroxyindane and after adding to the solution 1.4 g. of benzoyl chloride, the mixture was refluxed for 4 hours. After cooling the reaction mixture, the crystals precipitated Were recovered by filtration and recrystallized from an ethanol-ethyl acetate to obtain 2.5 g. of 1- benzoyloxy-Z-diethylaminoindane hydrochloride having a melting point of 197-198 C. (decomposed).

Elemental analysis as C H NO CI. Calculated (percent): C, 69.45; H, 6.99; N, 4.05. Found (percent): C, 69.36; H, 6.78; N, 4.21.

Example 8 In 10 ml. of dichloromethane was dissolved 0.7 g. of cis-l-hydroxy-2-dimethylamino Tetralin and after adding to the solution 0.8 g. of 4-dimethylaminobenzoylchloride hydrochloride, the mixture was refluxed for 8 hours and then the solvent was distilled off under reduced pressure. A small amount of water was added to the residue thus obtained and the crystals precipitated were recovered by filtration to obtain 0.8 g. of cis-Z-dimethylamino-l-(4- dimethylaminobenzoyloxy Tetralin hydrochloride. By recrystallizing the product from an ethanol-ethyl acetate solvent, the pure crystals of the product having a melting point of 2l5-216 C. (decomposed) were obtained.

Elemental analysis as C H N O CL /z H O. Calculated (percent): C, 65.70; H, 7.35; N, 7.30. Found (percent): C, 65.69; H, 7.11; N, 7.34.

Example 9 In 27.5 ml. of dichloromethane was dissolved 1.9 g. of cis-1-hydroxy 2 dimethylamino Tetralin and after adding to the solution 2.8 g. of 4-acetamino-5-chloro-2- methovybenzoylchloride, the mixture was refluxed for 8 hours. The solvent was distilled off under reduced pressure and after adding to the residue thus obtained ,100 ml. of 0.1 N sodium carbonate, the product was extracted three times each time with 20 ml. of ethyl acetate. The extract was dried over anhydrous potassium carbonate and then the solvent was distilled oif under reduced pressure. By purifying the residue by means of a silica gel column chromatography, 2 g. of oily cis-1-(4-acetamino-5 chloro-2-methoxybenzoyloxy) 2-dimethylamino Tetralin was obtained.

Elemental analysis as C H N O Cl. Calculated (per cent): C, 63.38; H, 6.04; N, 6.72. Found (percent): C, 63.46; H, 6.21; N, 6.53.

Example 10 In 13 ml. of dichloromethane was dissolved 0.9 g. of cis-1-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1 g. of 2-methoxy-4-nitrobenzoylchloride, the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and 1 ml. of ethanol and 10 ml. of ether were added to the residue obtained. The crystals thus precipitated were recovered by filtration and washed with ether to obtain 1.8 g. of cis-l- (2-methoxy-4 nitrobenzoyloxy) 2 dimethylamino Tetralin hydrochloride. By recrystallizing the product from ethanol, the pure crystals having a melting point of 207- 208 C. (decomposed) were obtained.

Elemental analysis as C H N O Cl. Calculated (percent): C, 59.04; H, 5.70; N, 6.89. Found (percent): C, 59.27; H, 5.51; N, 6.98.

Example 11 In 5 ml. of dichloromethane was dissolved 1 g. of cisl-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1 g. of p-toluoylchloride, the mixture was allowed to stand overnight. The solvent was distilled oft under reduced pressure and then 5 ml. of benzene was added to the residue. The crystals thus precipitated were recovered by filtration to obtain 1.5 g. of cis-Z-dimethylamino-l-p-toluoyloxy Tetralin hydrochloride. By recrystallizing the product from an ethanol-ether solvent, the pure crystals having a melting point of 187-189 C. (decomposed) were obtained.

Elemental analysis as C H NO Cl. Calculated (percent): C, 69.45; H, 6.99; N, 4.05. Found (percent): C, 69.59; H, 6.78; N, 4.21.

Example 12 By following the same procedure as in Example 11 using 1 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and 1.1 g. of 3,4-dichlorobenzoylchloride, 1.8 g. of cis-1-(3,4-

dichlorobenzoyloxy) -2-dimethylamino Tetralin hydrochloride having a melting point of 182-183 C. (decomposed) was obtained.

Elemental analysis as C H NO Cl Calculated (percent): C, 56.95; H, 5.03; N, 3.50. Found (percent): C, 56.73; H, 5.21; N, 3.43.

Example 13 By following the same procedure as in Example 11 using 1 g. of cisl-hydroxy-Z-dimethylamino Tetralin and 1.1 g. of p-nitrobenzoylchloride, there was obtained 1.5 5 g. of cis-Z-dimethylamino-l-(p-nitrobenzoyloxy) Tetralin hydrochloride having a melting point of 173-175 C. (decomposed).

Elemental analysis as C H N O Cl. Calculated (percent): C, 60.56; H, 5.62; N, 7.43. Found (percent): C, 60.67; H, 5.46; N, 7.58

Then, the hydrochloride prepared above was suspended in water and then the suspension was made alkaline with 2 N sodium carbonate and the product was extracted with dichloromethane. After drying over the extract, the solvent was distilled off under reduced pressure to obtain oily cis-Z-dimethylaminol-(p-nitrobenzoyloxy) Tetralin in the form of the free base.

Example 14 In 6.4 ml. of dichloromethane was dissolved 0.44 g. of cisl-hydroxy-Z-dimethylamino Tetralin and after adding to the solution 0.5 g. of p-phenylbenzoylchloride, the mixture was refluxed for 4 hours. The reaction mixture was, then, treated as in Example 11 to obtain 0.8 g. of cis-Z-dimethylamino-l-(p-phenylbenzoyloxy) Tetralin hydrochloride. The crystals of the product recrystallized from isopropanol had a melting point of 210-212" C. (decomposed).

Elemental analysis as C H NO Cl. Calculated (percent): C, 73.61; H, 6.42; N, 3.43. Found (percent): C, 73.74; H, 6.58; N, 3.31.

Example 15 By following the same procedure as in Example 14 using 1.6 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and 2.3 g. of 3,4,S-trimethoxybenzoylchloride, there was ob-- tained 3.6 g. of cis-1-(3,4,5-trimethoxybenzoyloxy)-2-dimethylamino Tetralin hydrochloride having a melting point of 147-149 C. (decomposed).

Elemental analysis as C H NO CL Calculated (percent): C, 62.63; H, 6.69; N, 3.32. Found (percent): C, 62.52; H, 6.75; N, 3.19.

Example 16 In 5 ml. of dichloromethane was dissolved 0.462 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and after adding to the solution 0.5 g. of o-methoxybenzoyl chloride, the mixture was refluxed for 5 hours. The solvent was distilled off from the reaction mixture under reduced pressure and the residue thus obtained was mixed with 10 ml. of benzene and 10 ml. of water followed by shaking. The aqueous layer thus formed was recovered and after making alkaline the aqueous layer with the addition of potassium carbonate, the product was extracted twice each time with 10 ml. of ether. After drying the ether extract obtained over anhydrous potassium carbonate, the solvent was distilled off under reduced pressure and when the residue was purified by means of a silica .gel column chromatography, an oily product was obtained. By adding ethanol hydrogenchloride to the oily product and distilling off the solvent, 0.4 g. of oily cis-1-(o-methoxybenzoyloxy)-2-dimethylamino Tetralin hydrochloride was obtained.

Elemental analysis as C H NO Cl. Calculated (percent): C, 66.48; H, 6.88; N, 3.87. Found (percent): C, 66.17; -H, 6.42; N, 3.54.

Example 17 By following the same procedure as in Example 16 using 2 g. of the cis-2-diethylamino-1-hydroxy Tetralin prepared by ethylating cis-2-ethylamino-1-hydroxy Tetralin and 1.42 g. of benzoylchloride, 2.5 g. of oily l-benzoyloxy-2-diethylamino Tetralin hydrochloride was obtained.

Elemental analysis as C H NO Cl. Calculated (percent): C, 66.38; H, 6.88; N, 3.87. Found (percent): C, 70.26; H, 7.02; N, 3.58.

Example 18 A mixture of l g. of cis-2-dimethylamino-l-(p-nitrobenzoyloxy) Tetralin, 1 g. of iron powder, 10 ml. of ethanol, 3 ml. of water, and two drops of concentrated hydrochloric acid was heated to C. for 25 minutes with stirring and then after adding to the mixture 0.5 g. of sodium bicarbonate, undissolved materials were filtered off. Then, ethanol was distilled off from the filtrate under reduced pressure, the crystals thus precipitated were recovered by filtration to provide 0.5 g. of cis-l-(p-aminobenzoyloxy)-2-dimethylamino Tetralin. The crystals of the product purified by recrystallizing from benzene had a melting point of 160-161" C.

Elementary analysis as C H N O Calculated (percent): C, 73.52; H, 7.14; N, 9.02. Found (percent): C, 73.66; H, 7.03; N, 9.18.

Example 19 By following the same procedure as in Example 18 using 1.5 g. of cis-1-(2-methoxy-4-nitrobenzoyloxy)-2-dimethylamino Tetralin hydrochloride, 0.9 g. of cis-l-(4- amino-2-methoxybenzoyloxy)-2 dimethylamino Tetralin having a melting point of 202203 C. was obtained.

Elemental analysis as C H N O Calculated (percent): C, 70.57; H, 7.11; N, 8.23. Found (percent): C, 70.39; H, 7.25; N, 8.04.

Example 20 To a mixture of 2 ml. of formic acid and 2 ml. of 37% formalin was added 2 g. of cis-2-phenyl-3a,4,5,9btetrahydronaphtho[2,1-d] oxazole and the mixture was heated to -105 C. for 8 hours. The reaction mixture was mixed with 10 ml. of water and after making the mixture alkalin with aqueous sodium carbonate solution, the product was extracted with 20 ml., 10 ml., and then, 10 ml. of ether successively. The-ether extracts were combined and dried over anhydrous magnesium sulfate. After adding to the mixture ethanol-hydrogenchloride, the sol- Vent. was distilled off to obtain 0.97 g. of cis-l-benzoyloxy- Z-dimethylamino Tetralin hydrochloride havin a melting point of 211-212 C.

Elemental analysis as C H NO C1. Calculated (P ?r cent): C, 68.77; H, 6.68; N, 4.22. Found (percent): C, 68.64; H, 6.61; N, 4.35.

'The free base of the hydrochloride obtained above was used as the sample for the analysis by nuclear magnetic resonance spectra.

Nuclear magnetic resonance spectrum 7:3.37 (doublet, J-=2-3 Hz., CDCl No absorption of 7:356 (doublet, J=8 Hz., CDCl of the transform was observed.

Production of Starting Material (a) In 20 ml. of water was dissolved 2 g. of 2-amino-ltetralonhydrochloride and after adding to the solution 2 ml. of ethyl acetate solution containing 1.7 g. of benzoyl chloride, the mixture was stirred while adding further 10% aqueous sodium hydroxide solution so that the pH of the system was maintained at 4 5. The crystals precipitated were recovered by filtration, washed with water, and dried to obtain 2.5 g. of 2-benzoylarnino-1-tetralon having a melting point of 180-181" C.

Elemental analysis as C H NO Calculated (percent): C, 76.96; H, 5.70; N, 5.28. Found (percent): C, 76.95; H, 5.75; N, 5.36.

(b) In 50 ml. of methanol was suspended 2.65 g. of 2- benzoylamino-l-tetralon and while cooling with ice Water, 0.4 g. of sodium borohydride was added to the suspension with stirring. After stirring for 2 hours, the reaction mixture was concentrated to 5 ml. and the crystals thus precipitated were recovered by filtration to obtain 2.4 g. of the crude crystals of trans-2-benzoylamino-l-hydroxy Tetralin, and the crystals contained cis-2-benzoylamino-1- hydroxy Tetralin in amount of 20% Nuclear magnetic resonance spectrum 1:4.63 (doublet, J-=8 Hz., pyridine-D 0) trans 1-=4.82 (doublet, J =3 Hz., pyridine-D 0) cis Furthermore, by recrystallizing the product from methanol, trans-Z-benzoylamino-1-hydroxy Tetralin having a melting point of 201-202 C. was obtained.

Elemental analysis as C H NO Calculated (percent): C, 76.38; H, 6.41; N, 5.24. Found (percent): C, 76.42; H, 6.38; N, 5.34.

(c) To 1 g. of crude trans-2-benzoylamino-l-hydroxy Tetralin was added 1.5 ml. of concentrated sulfuric acid under ice cooling and stirred for 2 hours. The reaction mixture was poured in a cold aqueous sodium carbonate solution and then extracted with 20 ml. and then 10 ml. of chloroform successively. The extracts were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off to provide 0.93 g. of oily cis-2-phenyl-3a,4,5, 9b-tetrahydronaphtho [2,1-d]oxazole.

16 Elemental analysis as C H NO. Calculated (percent) C, 81.90; H, 6.06; N, 5.62. Found (percent): C, 79.41; H, 5.86; N, 5.71.

Example 21 To 2 g. of cis-Z-amino-l-benzoyloxy Tetralin sulfate, were added 2 ml. of formic acid, 2 ml. of formaline, and 0.45 g. of sodium formate and the mixture was heated to 105 C. for 8 hours. After making the reaction mixture alkaline with the addition of aqueous sodium carbonate solution, the product was extracted with 20 ml. and then 10 ml. of chloroform. The extracts were combined with each other and dried over anhydrous magnesium sulfate. After adding to the solution ethanol-hydrogenchloride, the solvent was distilled olf to obtain 1.3 g. of the crystals of cis-1-benzoyloxy-2-dimethylamino Tetralin hydrochloride having a melting point of 211212 C.

The free base form of the hydrochloride was used as the sample of the analysis by the nuclear magnetic resonance spectra.

Nuclear magnetic resonance spectrum COO-Q Production of Starting Material In a mixture of 40 ml. of 1 normal sulfuric acid and 40 ml. of water was dissolved 9 g. of cis-2-phenyl-3a,4,5, 9b-tetrahydronaphtho[2,1-d] oxazole and the solution was allowed to stand overnight. The crystals precipitated were recovered by filtration to obtain 6 g. of cis-2-amino-1- benzoyloxy Tetralin sulfate. Furthermore, when the mother liquor was allowed to stand overnight, 1.5 g. of the above-mentioned product was also obtained.

The melting point of the product was 148-149 C.

Elemental analysis as C H NO /zH SO /2H O. Calculated (percent): C, 62.75; H, 5.89; N, 4.30. Found (percent): C, 62.76; H, 5.61; N, 4.25.

Nuclear magnetic resonance spectrum 1:3.35 (doublet, J-=3.35 Hz., D 0).

No absorption of the trans-form was observed.

Example 22 In 27.5 ml. of dichloromethane was dissolved 1.9 g. of cis-1-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1.9 g. of cinnamoyl chloride, the mixture was refluxed for 3 hours. The solvent was distilled olf under reduced pressure from the reaction mixture and the residue was mixed with 2 ml. of benzene, 2 ml. of ethyl acetate, 10 ml. of ether, and 1 ml. of-water. The crystals precipitated were recovered by filtration and washed with ether to obtain 3.25 g. of cis-l-cinnamoyloxy-Z-dimethylamino Tetralin hydrochloride. The crystals recrystallized from Water had a melting point of 100-105 C.

Elemental analysis as C H NO Cl-H O. Calculated (percent): C, 67.10; H, 6.97; N, 3.73. Found (percent): C, 66.50; H, 6.57; N, 4.17.

What is claimed is:

1. The l-benzoyloxy-Z-lower alkyl aminobenzocycloalkane derivatives represented by the formula N l C 9n wherein R represents hydrogen atom or a lower alkyl group; R represents a lower alkyl group; R R and R are same or difierent from each other and each represents hydrogen atom, a halogen atom, a lower alkyl group, a 15 2. Cis-l-benzoyloxy-Z-dimethylamino Tetralin.

3. Cis-1-benzoyloxy-Z-dimethylaminoindane.

4. Cis 1 benzoyloxy-Z-dimethylamino Tetralin hydrochloride.

5. Cis-1-benzoyloxy-Z-dimethylaminoindane hydrochloride.

6. Trans-1-benzoyloxy-Z-dimethylamino Tetralin.

References Cited Gonzales, A. et al.: Anales. Soc. Espfin. fis Quim. 20 534-8 (1922).

LORRAINE A. WEINBERGER, Primary Examiner P. J. KILLOS, Assistant Examiner US. Cl. X.R. 

